PML-controlled responses in severe congenital neutropenia with ELANE-misfolding mutations

• Published in: Blood advances 2021-02, Vol.5 (3), p.775-786
• Main Authors: Olofsen, Patricia A., Bosch, Dennis A., Roovers, Onno, van Strien, Paulina M.H., de Looper, Hans W.J., Hoogenboezem, Remco M., Barnhoorn, Sander, Mastroberardino, Pier G., Ghazvini, Mehrnaz, van der Velden, Vincent H.J., Bindels, Eric M.J., de Pater, Emma M., Touw, Ivo P.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Congenital Bone Marrow Failure Syndromes; Granulocyte Colony-Stimulating Factor; Hematopoiesis and Stem Cells; Humans; Leukocyte Elastase - genetics; Mutation; Neutropenia - congenital; Neutropenia - genetics
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2020003214

Mutations in ELANE cause severe congenital neutropenia (SCN), but how they affect neutrophil production and contribute to leukemia predisposition is unknown. Neutropenia is alleviated by CSF3 (granulocyte colony-stimulating factor) therapy in most cases, but dose requirements vary between patients. Here, we show that CD34+CD45+ hematopoietic progenitor cells (HPCs) derived from induced pluripotent stem cell lines from patients with SCN that have mutations in ELANE (n = 2) or HAX1 (n = 1) display elevated levels of reactive oxygen species (ROS) relative to normal iPSC-derived HPCs. In patients with ELANE mutations causing misfolding of the neutrophil elastase (NE) protein, HPCs contained elevated numbers of promyelocyte leukemia protein nuclear bodies, a hallmark of acute oxidative stress. This was confirmed in primary bone marrow cells from 3 additional patients with ELANE-mutant SCN. Apart from responding to elevated ROS levels, PML controlled the metabolic state of these ELANE-mutant HPCs as well as the expression of ELANE, suggestive of a feed-forward mechanism of disease development. Both PML deletion and correction of the ELANE mutation restored CSF3 responses of these ELANE-mutant HPCs. These findings suggest that PML plays a crucial role in the disease course of ELANE-SCN characterized by NE misfolding, with potential implications for CSF3 therapy. •PML reduces ROS but stimulates metabolism and ELANE expression in iPSC-derived CD34+CD45+ cells from ELANE-SCN with NE misfolding mutations.•PML dampens granulocyte colony-stimulating factor responsiveness in a CSF3 therapy-refractory case of ELANE-SCN. [Display omitted]